The present invention relates to polycyclic ether antibiotics. This family of antibiotics includes such well known agents as monensin, nigericin, grisorixin, dianemycin, maduramycin, narasin, salinomycin, lasalocid, mutalomycin, ionomycin and leuseramycin. The subject has been reviewed by Westley, "Polyether Antiobiotics", Adv. Appl. Microbiol., 22, 177, 1977.
The polycyclic ether antibiotics listed above are active against Gram-positive bacteria, fungi and protozoa. In particular these antibiotics exhibit potent anti-coccidial activity. They have therefore been employed with varying degrees of success in the treatment of a variety of animal infections.
The protozoan disease, coccidiosis, continues to be a serious problem and its control is of economic importance to veterinary science, especially to the poultry industry. Coccidiosis results from infection by one or more species of Eimeria or Isospora (for a summary, see Lund and Farr in "Diseases of Poultry," 5th ed., Biester and Schwarte, Eds., Iowa State University Press, Ames, Iowa, 1965, pages 1056-1096). There are six species of coccidia which produce morbidity in susceptible chickens. Eimeria tenella, E. necatrix, E. brunetti, E. acervulina, E. maxima and E. mivati produce damage either directly through destruction of epithelial cells of the digestive tract or indirectly through production of toxins. Three other species of protozoa, E. mitis, E. hagani and E. praecox, belonging to the same genus are considered to be relatively innocuous. However, these species are capable of reducing weight gain, lowering feed efficiency and adversely affecting egg production.
In view of the great economic losses due to coccidiosis, the search for new anticoccidial agents continues.
Enteritis is another disease which can cause severe economic losses to livestock producers. Enteritis occurs in chickens, swine, cattle and sheep and is attributed mainly to anaerobic bacteria, particularly Clostridium perfringens, and viruses. Enterotoxemia in ruminants, an example of which is "overeating disease" in sheep, is a condition caused by C. perfringens infection.
Swine dysentery is one of the most common swine diseases diagnosed in the United States. Additionally, the disease is prevalent in many other countries and annually causes considerable losses in stock to swine growers around the world. Treponema hyodysenteriae, a large spirochete, has been shown to be capable of producing the disease (see Harris, D. L. et al. "Swine Dysentery-1, Inoculation of Pigs with Treponema hyodysenteriae (New Species) and Reproduction of the Disease," Vet. Med/SAC, 67, 61-64 (1972)) Although it is not known whether T. hyodysenteriae is the sole causative organism of swine dysentery, it can be concluded from the data available, that it is a primary source of the infection.
Performance enhancement (increased rate of growth and/or increased efficiency of feed utilization) in ruminants such as cattle, and in monogastric animals such as swine, is another economically desirable objective of veterinary science. Of particular interest is improved performance achieved by increasing the efficiency of feed-utilization. The mechanism for utilization of the major nutritive portion of ruminant feeds is well known. Micro-organisms in the rumen of the animal degrade carbohydrates to produce monosaccharides and then convert these monosaccharides to pyruvate compounds. Pyruvates are metabolized by microbiological processes to form acetates, butyrates or propionates, collectively known as volatile fatty acids. For a more detailed discussion, see Leng in "Physiology of Digestion and Metabolism in the Ruminant," Phillipson et al, Eds., Oriel Press, Newcastle-upon-Tyne, England, 1970, pages 408-410.
The relative efficiency of volatile fatty acid utilization is discussed by McCullough in "Feedstuffs", Jun. 19, 1971, page 19; Eskeland et al. in J. An. Sci., 33, 282 (1971); and Church et al. in "Digestive Physiology and Nutrition of Ruminants", Vol. 2, 1971, pages 622 and 625. Although acetates and butyrates are utilized, propionates are utilized with greater efficiency. Furthermore, when too little propionate is available, animals may develop ketosis. A beneficial compound, therefore, stimulates animals to produce a higher proportion of propionates from carbohydrates, thereby increasing carbohydrate utilization efficiency and also reducing the incidence of ketosis.
The compounds of the present invention may be prepared by alkylation of the acidic polycyclic ether antibiotic designated as UK-58,852 having the formula ##STR2## wherein Me is methyl. The antibiotic UK-58,852 is disclosed in European Patent Application Publication No. 0169011. The antibiotic is produced by the submerged aerobic propagation in aqueous nutrient media of the microorganism Actinomadura roseorufa Huang sp. nov., ATCC 39697 isolated from a soil sample from Japan.